This invention provides a method for identifying compounds potentially useful for the treatment and prevention of pre-cancerous and cancerous lesions in mammals. This application is a continuation of U.S. patent application Ser. No. 08/866,027 to Piazza et al. Filed May 30, 1997.
Familial adenomatous polyposis ("FAP") is an inherited disease where the victim's colon contains many polyps or adenomas virtually uncountable in most instances. Because such patients develop so many polyps or adenomas each of which has a significant risk of developing into a cancer--the typical treatment is surgical removal of the colon. In about 1983, Waddell discovered that the nonsteroidal anti-inflammatory drug ("NSAID") sulindac would cause colonic polyps (a type of pre-cancerous lesion) to regress and prevent their recurrence when that drug was administered to patients with FAP. Waddell's experience with sulindac in FAP patients was confirmed in several subsequent studies. Unfortunately, since sulindac and other NSAIDS aggravate the digestive tract (not to mention side effects involving kidney and interference with normal blood clotting) of patients to whom it has been chronically administered, it is not a practical treatment for FAP or any other cancer or precancerous indication (i.e., neoplasia) requiring long-term administration.
Waddell originally hypothesized that the mechanism of action of sulindac on colonic polyps involved the inhibition of the synthesis of prostaglandin (PG). (Waddell, W. R. et al., "Sulindac for Polyposis of the Colon," Journal of Surgical Oncology, 24:83-87, 1983). Prostaglandin ("PG") synthesis inhibition results from the inhibition of cyclooxygenase (COX) caused by NSAIDs. A common benefit of NSAIDs is the reduction of inflammation, which is known to be caused by the reduction of PG levels. Since NSAIDs are known to inhibit COX, which inhibits PG synthesis, it is widely believed that the regression of colonic polyps is attributed to this property. In fact, notwithstanding recent discoveries to the contrary, it has become conventional wisdom that administration of an inhibitor of PG synthesis (e.g., an NSAID) to a patient with FAP or other precancerous or cancerous lesion will result in the regression of the lesion due to a reduction of PG levels.
Recent discoveries, however, are leading scientists in a completely different direction--that it is not necessary to inhibit COX to treat neoplasia patients successfully. Pamukcu et al., in U.S. Pat. No. 5,401,774, disclosed that sulfonyl compounds, that were previously reported to be inactive as PG synthesis inhibitors (and therefore not an NSAID or an anti-inflammatory compound) unexpectedly inhibited the growth of a variety of neoplastic cells, including colon polyp cells. These sulfonyl derivatives have proven effective in rat models of colon carcinogenesis, and one variant (now referred to as exisulind) has proven effective in preliminary human clinical trials with FAP patients.
The importance of this discovery--and the de-linking of anti-neoplasitic activity and COX inhibition--cannot be overstated. If those two phenomena were related, there would be little hope for a safe NSAID therapy for FAP patients because the side effects of NSAIDs, such as gastric irritation, are also caused by COX inhibition. Prostaglandins play a protective function in the lining of the stomach. When NSAIDs are administered, COX is inhibited and PG levels are reduced: gastric irritation is a common result. Those side effects may not manifest themselves in short-term (acute) NSAID therapy. However, during long-term (chronic) NSAID therapy, gastric irritation, bleeding and ulceration are very common. In significant numbers of cases, NSAID therapy must be stopped due to the severity of those side effects and other potentially lethal side effects. Furthermore, the severity of such side effects increases with age, probably because natural PG levels in gastric mucosa falls with age. Thus, useful compounds for treating neoplastic lesions should desirably inhibit neoplastic cell growth, but should not inhibit COX.
Conventional methods for screening compounds may be used to find improved compounds that inhibit neoplastic cell growth. Under this scenario, drugs may be screened using in vitro models. But conventional in vitro screening methods could pass many compounds that later are shown to be ineffective in animal models because of a number of unanticipated problems, one of which may be that the in vitro screen is not predictive of efficacy. Animal model studies are time consuming and expensive. Therefore, a more precise in vitro screening method that provides predictive information for treating neoplasia is needed to screen compounds prior to human testing. Knowledge of a specific target for inhibiting human cancer would allow for greater precision and efficiency whereby highly effective and safe compounds can be identified prior to animal testing.
Presently, rational drug discovery methods are being applied in the pharmaceutical industry to improve methods for identifying clinically useful compounds. Typically, rational drug discovery methods relate to a "lock and key" concept whereby structural relationships between a therapeutic target molecule (lock) and pharmaceutical compounds (key) are defined. Such methods are greatly enhanced by specialty computer software that accesses databases of compounds to identify likely geometric fits with the target molecule. Unfortunately, to use these systems, one has to have insight to the target molecule (lock). The target may be an enzyme, a protein, a membrane or nuclear receptor, or a nucleic acid sequence, for example.
In complex diseases, such as neoplasia, scientists have identified a number of potential targets. However, many of the drugs available for the treatment of neoplasia are non-specific and toxic to normal tissues, and are not indicated for precancer and used only when neoplastic cells progress to cancer. Greater understanding of the mechanisms involved in cancer may lead scientists on the path towards designing more specific antineoplastic drugs--drugs that can safely be administered earlier in the disease process.